Identification of serum protein biomarkers by profiling N-glycoproteomes of patient-derived xenografts of neuroendocrine prostate cancer

通过分析神经内分泌前列腺癌患者来源的异种移植物的 N-糖蛋白质组来鉴定血清蛋白生物标志物

• 批准号: 10572514
• 负责人: JAMES D. BROOKS
• 金额: $ 21.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572514
• 关键词: Adenocarcinoma; Benign Prostatic Hypertrophy; Bioinformatics; Biological Assay; Biological Markers; Biopsy; Cancer Histology; Cancer Patient; Castration; Cell surface; Clinic; Clinical; Clinical Trials; Cryopreservation; Cryopreserved Tissue; Databases; Development; Disease; Extracellular Matrix; Foundations; Fractionation; Future; Glycopeptides; Glycoproteins; Goals; Histologic; Human; Image; Immunodeficient Mouse; International; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Measures; Methods; Monitor; Monitoring for Recurrence; Mus; Neuroendocrine Prostate Cancer; Non-Invasive Detection; Pathologic; Patient Monitoring; Patient Selection; Patient Triage; Patients; Peptides; Pharmaceutical Preparations; Procedures; Prostate Adenocarcinoma; Protein Glycosylation; Protein Isoforms; Proteins; Proteomics; Quality of life; Reaction; Resistance; Resolution; Resources; Sampling; Sensitivity and Specificity; Series; Serum; Serum Proteins; Systemic Therapy; Testing; Time; Tumor Subtype; Tumor Tissue; Tumor Volume; Validation; Variant; androgen deprivation therapy; biomarker discovery; cancer biomarkers; candidate marker; candidate selection; candidate validation; chemotherapy; cohort; glycoproteomics; glycosylation; implantation; improved; individualized medicine; mass spectrometer; novel; novel strategies; novel therapeutics; patient derived xenograft model; patient response; potential biomarker; profiles in patients; programs; protein biomarkers; protein complex; resistance mechanism; response; specific biomarkers; standard of care; targeted treatment; therapy development; treatment response; tumor; tumor xenograft

PROJECT SUMMARY Neuroendocrine prostate cancer (NEPC) is a lethal variant of prostate cancer (PCa) that may arise de novo or in 17-30% of patients previously treated with standard of care androgen deprivation therapy (ADT) for prostate adenocarcinoma (AC) as a mechanism of resistance. Serum biomarkers with high sensitivity and specificity for non-invasive detection for NEPC are urgently needed to enable clinicians to select the proper next-line systemic therapy in a timely manner, select of patients for clinical trials, and monitor treatment responses that entail reversing the NEPC state. A novel strategy that allows quick identification of ‘‘human- unique’’ proteins in a mouse serum background, thereby overcoming limitations associated with proteomics- based biomarker discovery, has been used successfully to identify serum glycoprotein biomarkers in ovarian cancer patient-derived xenografts (PDX). We hypothesize that PCa PDX tumors that reflect human PCa express unique tumor-associated glycoproteins that can be readily identified in sera of tumor-bearing mice using mass spectrometry. Moreover, different serum glycoproteins and their levels are associated with different subtypes of PCa PDXs, namely, pure AC, AC mixed with NEPC, and pure NEPC. Finally, these subtype specific biomarkers can be used to identify NEPC in clinical samples from PCa patients. In Aim 1, we will identify novel serum glycoproteins associated with subtypes of PCa PDX tumors by glycoproteomic analyses of PDX sera. Specifically, PDX tumors will be generated using cryopreserved tissues from publically available PDXs lines with pure AC, AC mixed with NEPC and pure NEPC histology by subrenal implantation into immunodeficient mice. Quantitative proteomics will be performed to generate glycoproteomic profiles of PDX sera and human-specific proteins will be selected bioinformatically. In Aim 2, serum proteins found in samples with a NEPC component but not expressed in pure AC samples will be selected. The top 5 candidate NEPC-specific biomarkers for which a targeted assay is developed successfully will be validated in sera from PDX mice and patients with pathologically confirmed NEPC component. The sensitivity and specificity of these biomarkers will be assessed using sera from patients with pathologically confirmed AC and benign prostatic hyperplasia as true negative control. Our approach would lead to biomarkers that could be developed quickly for use in the clinic to reduce morbid biopsies and appropriately triage patients to therapies tailored to their disease state, which in turn, will improve quality of life and survival. In addition, these biomarkers could be used to monitor patient response to standard-of-care therapies and select patients for clinical trials testing novel therapies developed in the future that target NEPC specifically. Moreover, the subtype-specific glycoproteins we identified could serve as the basis for future imaging strategies or targeted therapies. Finally, the glycoproteomes of NEPC will provide a valuable resource for better understanding the mechanisms of NEPC development.

项目摘要 神经内分泌前列腺癌（NEPC）是前列腺癌（PCa）的一种致死性变异，可能发生于晚期。 初治或17 - 30%既往接受过标准雄激素剥夺治疗（ADT）的患者， 前列腺腺癌（AC）作为耐药机制。具有高灵敏度的血清生物标志物， NEPC的非侵入性检测的特异性是迫切需要的，以使临床医生能够选择适当的 及时进行下一线系统治疗，选择患者进行临床试验，并监测治疗 需要扭转NEPC状态的反应。一种新的策略，可以快速识别"人类- 小鼠血清背景中的独特蛋白质，从而克服了与蛋白质组学相关的局限性- 基于生物标志物发现，已成功用于鉴定卵巢癌患者血清糖蛋白生物标志物。 癌症患者来源的异种移植物（PDX）。我们假设PCa PDX肿瘤反映了人类PCa 表达独特的肿瘤相关糖蛋白，这些糖蛋白可以在荷瘤小鼠的血清中容易地鉴定 使用质谱法。此外，不同的血清糖蛋白及其水平与不同的 PCa PDX的亚型，即纯AC、AC与NEPC混合和纯NEPC。最后，这些子类型 特异性生物标志物可用于鉴定来自PCa患者的临床样品中的NEPC。 在目标1中，我们将通过以下方法鉴定与PCa PDX肿瘤亚型相关的新型血清糖蛋白： PDX血清的糖蛋白质组学分析。具体而言，将使用冷冻保存的组织生成PDX肿瘤 从肾下移植的具有纯AC、AC与NEPC混合和纯NEPC组织学的可获得的PDX系中， 植入免疫缺陷小鼠。将进行定量蛋白质组学，以生成糖蛋白质组学 PDX血清和人特异性蛋白质的谱将被生物信息学地选择。目的2：血清蛋白 将选择在含有NEPC成分的样品中发现但在纯AC样品中不表达的。前5 成功开发靶向测定的候选NEPC特异性生物标志物将在 来自PDX小鼠和具有病理证实的NEPC组分的患者的血清。的敏感性和 这些生物标志物的特异性将使用来自病理学证实的AC患者的血清进行评估， 良性前列腺增生作为真阴性对照。 我们的方法将导致生物标志物，可以迅速开发用于临床，以减少 病理活检，并适当地将患者分类到针对其疾病状态的治疗，这反过来又会 提高生活和生存质量。此外，这些生物标志物可用于监测患者对以下药物的反应： 标准治疗和选择患者进行临床试验，测试未来开发的新疗法 专门针对NEPC。此外，我们鉴定的亚型特异性糖蛋白可以作为 为未来的成像策略或靶向治疗奠定基础。最后，NEPC的糖蛋白质组将提供一个 更好地理解NEPC发展机制的宝贵资源。